Antibody induction of lupus-like neuropsychiatric manifestations.

Although systemic lupus erythematosus (SLE) is usually evaluated with regard to autoimmune reactivity toward the kidney, there are multiple psychiatric abnormalities associated with this autoimmune disease. Lupus-prone male NZM88 mice, derived from NZB/NZW F1 mice, develop early neuropsychiatric manifestations without any signs of nephritis. In addition to the usual repertoire of antibody specificities, including autoantibodies to dsDNA and renal antigens, mice of this inbred strain express autoantibodies to numerous brain antigens. Here, we show that autoantibodies to brain antigens, assessed by Western analysis, are as individually varied as are the diverse neuropsychiatric manifestations observed in SLE patients. Additionally, a monoclonal antibody derived from the spleen of an untreated NZM88 male when injected into healthy BALB/cByJ, but not C57BL/6J, mice induced behaviors similar to those of lupus-prone NZM88 mice. This monoclonal antibody, which is specific to dynamin-1, binds preferentially in BALB/cByJ cortex and induces substantial expression of cytokines mainly in the hypothalamus. Thus, an antibody to just one brain antigen can induce multiple behavioral changes, and multiple autoantibodies to different brain antigens exist in lupus-prone mice; however, susceptibility to the induction of neurobehavioral deficits is dependent on host genetics.

Regional expression of constitutive and inducible transcription factors following transient focal ischemia in the neonatal rat: influence of hypothermia.

Ischemia is a potent modulator of gene expression. Differential expression of transcription factors after focal ischemia may reflect the potential for neuronal recovery in peri-ischemic regions. Previously, we demonstrated that hypothermia reduces the volume of damage in a model of neonatal focal ischemia. In the present study, immunocytochemistry was used to assess the temporal and spatial profiles of the transcription factors Fos and pCREB under normal and hypothermic conditions in this neonatal model of focal ischemia. At 7 days of age, rat pups underwent a permanent middle cerebral artery occlusion (MCAo) coupled with a temporary 1-h occlusion of the common carotid artery (CCAo). They were maintained at 37 degrees C throughout ischemia and reperfusion (Normothermic), or given 1 h of hypothermic conditions (28 degrees C) either during the occlusion (Intraischemic Hypothermia) or during the second hour of reperfusion (postischemic hypothermia). In normothermic pups, Fos immunoreactivity peaked at early time points (4-8 h post-ischemia) in a narrow band in peri-ischemic regions. By later stages of reperfusion (12-24 h), there was a more widespread induction in peri-ischemic regions including the ipsilateral cortex. In contrast with Fos, the constitutive transcription factor pCREB was reduced in core regions at all time points examined. Both the c-fos induction in peri-ischemic regions and the reduction of pCREB in the core were attenuated by intraischemic hypothermia. Postischemic hypothermia altered the distribution of Fos immunoreactivity without significantly changing the number of Fos- and pCREB-immunoreactive cells compared to normothermic rats. Both intra- and postischemic hypothermia reduced the number of caspase-immunoreactive cells. Thus, focal ischemia in the P7 rat produces different distributions of Fos and pCREB than what has been observed in adult rats subjected to focal ischemia, and expression of these transcription factors can be altered by hypothermia.

Protective effects of brief intra- and delayed postischemic hypothermia in a transient focal ischemia model in the neonatal rat.

Hypothermia provides neuroprotection in virtually all animal models of ischemia, including adult stroke models and the neonatal hypoxic-ischemic (HI) model. In these studies, brief periods of hypothermia are examined in a neonatal model employing transient focal ischemia in a 7-day-old rat pup. Pups underwent permanent middle cerebral artery (MCA) occlusion coupled with a temporary (1 h) occlusion of the ipsilateral common carotid artery (CCA). This study included five treatment groups: (1) normothermic (Normo)-brain temperature was maintained at 37 degrees C; (2) intraischemic hypothermia (IntraH)-28 degrees C during the 1-h ischemic period only; (3) postischemic hypothermia (PostH)-28 degrees C for the second hour of reperfusion only; (4) late-onset postischemic hypothermia (LPostH) cooled to 28 degrees C for the fifth and sixth hours of reperfusion only; and (5) Shams. After various times (3 days-6 weeks), the lesion was assessed using 2,3,5-triphenyltetrazolium chloride (TTC) or hematoxylin and eosin (H&E) stains. Intraischemic hypothermia resulted in significant protection in terms of survival, lesion size, and histology. Postischemic hypothermia was not effective in reducing lesion size early after ischemia, but significantly reduced the eventual long-term damage (2-6 weeks). Late-onset postischemic hypothermia did not reduce infarct volume. Therefore, both intraischemic and postischemic hypothermia provided neuroprotection in the neonatal rat, but with different effects on the degenerative time course. While there were no observable differences in simple behaviors or growth, all hypothermic conditions significantly reduced mortality rates. While the protection resulting from intraischemic hypothermia is similar to what is observed in other models, the degree of long-term ischemic protection observed after 1 h of postischemic hypothermia was remarkable and distinct from what has been observed in other adult or neonatal models.